Hydroxyfunctional amide 1h-indole derivatives active as sPLA2 inhibitors

ABSTRACT

A class of novel indole is disclosed together with the use of such compounds for inhibiting sPLA 2  mediated release of fatty acids for treatment of Inflammatory Diseases such as septic shock.

This application is a 371 of PCT/US00/20816 filed in English on 7 Sep.2000, which claims benefit of Ser. No. 60/154,836 filed Sep. 20, 1999.

FIELD OF THE INVENTION

This invention relates to novel indole compounds useful for InflammatoryDiseases.

BACKGROUND OF THE INVENTION

The structure and physical properties of human non-pancreatic secretoryphospholipase A₂ (hereinafter called, “sPLA₂”) has been thoroughlydescribed in two articles, namely, “Cloning and Recombinant Expressionof Phospholipase A₂ Present in Rheumatoid Arthritic Synovial Fluid” bySeilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley;Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal ofBiological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5335-5338,1989; and “Structure and Properties of a Human Non-pancreaticPhospholipase A₂” by Kramer, Ruth M.; Hession, Catherine; Johansen,Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard,Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry,Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosuresof which are incorporated herein by reference.

It is believed that sPLA₂ is a rate limiting enzyme in the arachidonicacid cascade which hydrolyzes membrane phospholipids. Thus, it isimportant to develop compounds which inhibit sPLA₂ mediated release offatty acids (e.g., arachidonic acid). Such compounds would be of valuein general treatment of conditions induced and/or maintained byoverproduction of sPLA₂; such as sepsis or rheumatoid arthritis.

It is desirable to develop new compounds and treatments for sPLA₂induced diseases.

SUMMARY OF THE INVENTION

This invention provides novel indole compounds having potent andselective effectiveness as inhibitors of mammalian sPLA₂.

This invention is also the use of novel indole compounds useful in thetreatment and prevention of Inflammatory Diseases.

This invention is also the use of novel indole compounds to inhibitmammalian sPLA₂ mediated release of fatty acids.

This invention is also a pharmaceutical composition containing any ofthe indole compounds of the invention.

I. Definitions

The term, “Inflammatory Diseases” refers to diseases such asinflammatory bowel disease, sepsis, septic shock, adult respiratorydistress syndrome, pancreatitis, trauma-induced shock, bronchial asthma,allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acutebronchitis, chronic bronchitis, acute bronchiolitis, chronicbronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosingspondylitis, Reiter's syndrome, psoriatic arthropathy, enterapathricspondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis,Reactive arthropathy, infectious or post-infectious arthritis,gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungalarthritis, syphilitic arthritis, Lyme disease, arthritis associated with“vasculitic syndromes”, polyarteritis nodosa, hypersensitivityvasculitis, Luegenec's granulomatosis, polymyalgin rheumatica, jointcell arteritis, calcium crystal deposition arthropathris, pseudo gout,non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tenniselbow), carpal tunnel syndrome, repetitive use injury (typing),miscellaneous forms of arthritis, neuropathic joint disease (charco andjoint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura,hypertrophic osteoarthropathy, multicentric reticulohistiocytosis,arthritis associated with certain diseases, surcoilosis,hemochromatosis, sickle cell disease and other hemoglobinopathries,hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism,acromegaly, familial Mediterranean fever, Behat's Disease, systemiclupus erythrematosis, or relapsing polychondritis and related diseaseswhich comprises administering to a mammal in need of such treatment atherapeutically effective amount of the compound of formula I in anamount sufficient to inhibit sPLA₂ mediated release of fatty acid and tothereby inhibit or prevent the arachidonic acid cascade and itsdeleterious products.

The term, “indole nucleus” refers to a nucleus (having numberedpositions) with the structural formula (X):

The indole compounds of the invention employ certain defining terms asfollows:

The term, “alkyl” by itself or as part of another substituent means,unless otherwise defined, a straight or branched chain monovalenthydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl,tertiary butyl, sec-butyl, n-pentyl, and n-hexyl.

The term, “alkenyl” employed alone or in combination with other termsmeans a straight chain or branched monovalent hydrocarbon group havingthe stated number range of carbon atoms, and typified by groups such asvinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.

The term, “hydrocarbyl” means an organic group containing only carbonand hydrogen.

The term, “halo” means fluoro, chloro, bromo, or iodo.

The term, heterocyclic radical, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted orunsubstituted heterocyclic nuclei having 5 to 14 ring atoms andcontaining from 1 to 3 hetero atoms selected from the group consistingof nitrogen, oxygen or sulfur. Typical heterocyclic radicals arepyrrolyl, pyrrolodinyl, piperidinyl, furanyl, thiophenyl, pyrazolyl,imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl,benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl,imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl,1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl,dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl,phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl,quinazolinyl, morpholino, thiomorpholino, homopiperazinyl,tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl,1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiopheneyl,pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl,azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl andquinoxalinyl.

The term, “carbocyclic radical” refers to radicals derived from asaturated or unsaturated, substituted or unsubstituted 5 to 14 memberedorganic nucleus whose ring forming atoms (other than hydrogen) aresolely carbon atoms. Typical carbocyclic radicals are cycloalkyl,cycloalkenyl, phenyl, spiro[5.5]undecanyl, naphthyl, norbornanyl,bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl,diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, andanthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologuesrepresented by the formula (a):

where n is a number from 1 to 8.

The term, “non-interfering substituent”, refers to radicals suitable forsubstitution at positions 4,5,6 and/or 7 of the indole nucleus and onother nucleus substituents (as hereinafter described for Formula I), andradicals suitable for substitution on the heterocyclic radical andcarbocyclic radical as defined above. Illustrative non-interferingradicals are C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₇-C₁₂ aralkyl,C₇-C₁₂ alkaryl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, phenyl, tolulyl,xylenyl, biphenyl, C₁-C₈ alkoxy, C₂-C₈ alkenyloxy, C₂-C₈ alkynyloxy,C₂-C₁₂ alkoxyalkyl, C₂-C₁₂ alkoxyalkyloxy, C₂-C₁₂ alkylcarbonyl, C₂-C₁₂alkylcarbonylamino, C₂-C₁₂ alkoxyamino, C₂-C₁₂ alkoxyaminocarbonyl,C₁-C₁₂ alkylamino, C₁-C₆ alkylthio, C₂-C₁₂ alkylthiocarbonyl, C₁-C₈alkylsulfinyl, C₁-C₈ alkylsulfonyl, C₂-C₈ haloalkoxy, C₁-C₈haloalkylsulfonyl, C₂-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, —C(O)O(C₁-C₈alkyl), —(CH₂)_(n)—O—(C₁-C₈ alkyl), benzyloxy, phenoxy, phenylthio,—(CONHSO₂R), —CHO, amino, amidino, bromo, carbamyl, carboxyl,carbalkoxy, —(CH₂)_(n)—CO₂H, chloro, cyano, cyanoguanidinyl, fluoro,guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo,nitro, phosphono, —SO₃H, thioacetal, thiocarbonyl, and carbonyl; where nis from 1 to 8 and R is C₁-C₈ alkyl.

The term, “organic substituent” refers to a monovalent radicalconsisting of carbon and hydrogen with or without oxygen, nitrogen,sulfur, halogen, or other elements. Illustrative organic substituentsare C₁-C₈ alkyl, aryl, C₇-C₁₄ aralkyl, C₇-C₁₄ alkaryl, C₃-C₈ cycloalkyl,C₁-C₈ alkoxyalkyl and these groups substituted with halogen, —CF₃, —OH,C₁-C₈ alkyl, amino, carbonyl, and —CN.

The term, “hydroxyfunctional amide” is a group represented by theformula:

wherein Y is oxygen, nitrogen or sulfur;

R^(4a) is selected from the group consisting of hydrogen, OH,(C₁-C₆)alkoxy, and aryloxy; and

wherein R^(4b) is hydrogen or an organic substituent selected from thegroup consisting of C₁-C₈ alkyl, aryl, C₇-C₁₄ aralkyl, C₇-C₁₄ alkaryl,C₃-C₈ cycloalkyl, C₁-C₈ alkoxyalkyl and these groups substituted withhalogen, —CF₃, —OH, C₁-C₈ alkyl, amino, carbonyl, and —CN.

The term “substituted group” is an organic group substituted with one ormore non-interfering substituents.

The words, “hydroxyfunctional amide linker” refer to a divalent linkinggroup symbolized as, —(L_(h))—, which has the function of joining the4-position of the indole nucleus to an hydroxyfunctional amide group inthe general relationship:

The words, “hydroxyfunctional amide linker length”, refer to the numberof atoms (excluding hydrogen) in the shortest chain of the linking group—(L_(h))— that connects the 4-position of the indole nucleus with thehydroxyfunctional amide group. The presence of a carbocyclic ring in—(L_(h))— counts as the number of atoms approximately equivalent to thecalculated diameter of the carbocyclic ring. Thus, a benzene orcyclohexane ring in the acid linker counts as 2 atoms in calculating thelength of —(L_(h))—. Illustrative hydroxyfunctional amide linker groupsare;

wherein, groups (a), (b) and (c) have acid linker lengths of 5, 7, and2, respectively.

The term, “(acidic group)” means an organic group which when attached toan indole nucleus at position 5, through suitable linking atoms(hereinafter defined as the “acid linker”), acts as a proton donorcapable of hydrogen bonding. Illustrative of an (acidic group) are thefollowing:

where n is 1 to 8, R₈₀ is a metal or C₁-C₈ and R₈₁ is an organicsubstituent or —CF₃.

The words, “acid linker” refer to a divalent linking group symbolizedas, —(L_(a))—, which has the function of joining the 5 position of theindole nucleus to an acidic group in the general relationship:

The words, “acid linker length”, refer to the number of atoms (excludinghydrogen) in the shortest chain of the linking group —(L_(a))— thatconnects the 5 position of the indole nucleus with the acidic group. Thepresence of a carbocyclic ring in —(L_(a))— counts as the number ofatoms approximately equivalent to the calculated diameter of thecarbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linkercounts as 2 atoms in calculating the length of —(L_(a))—. Illustrativeacid linker groups are;

wherein, groups (a), (b), and (c) have acid linker lengths of 5, 7, and2, respectively.

The term, “amine”, includes primary, secondary and tertiary amines.

The terms, “mammal” and “mammalian” include human and domesticatedquadrupeds.

The term, “alkylene chain of 1 or 2 carbon atoms” refers to the divalentradicals, —CH₂—CH₂— and —CH₂—.

The term, “group containing 1 to 4 non-hydrogen atoms” refers torelatively small groups which form substituents at the 2 position of theindole nucleus, said groups may contain non-hydrogen atoms alone, ornon-hydrogen atoms plus hydrogen atoms as required to satisfy theunsubstituted valence of the non-hydrogen atoms, for example; (i) groupsabsent hydrogen which contain no more than 4 non-hydrogen atoms such as—CF₃, —Cl, —Br, —NO₂, —CN, —SO₃; and (ii) groups having hydrogen atomswhich contain less than 4 non-hydrogen atoms such as —CH₃, —C₂H₅, and—CH═CH₂.

The term “oxime amide” means the radical, —C═NOR—C(O)NH₂.

The term “thio-oxime amide” means the radical —C═NOR—C(S)—NH₂.

The term “spiro[5.5]undecanyl” refers to the group represented by theformula;

II. The Hydroxyfunctional Amide 1H-indole Compounds of the Invention

The present invention provides novel classes of indole compounds usefulas sPLA₂ inhibitors for the treatment of inflammation. Classes of indolecompounds of this invention include indole glyoxylamide hydroxyfunctional amide derivatives, indole-3-oxime amide hydroxy functionalamide derivatives and indole acetamide hydroxy functional amidederivatives. The compounds of the invention have the general formula (I)or a pharmaceutically acceptable salt, solvate or prodrug thereof;

wherein;

R₁ is selected from groups (a), (b), and (c) wherein;

(a) is C₇-C₂₀ alkyl, C₇-C₂₀ haloalkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl,carbocyclic radical, carbocyclic radical substituted withnon-interfering substituents or heterocyclic radical, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents;

(c) is the group —(L)—R₈₀; where, —(L)— is a divalent linking group of 1to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, andsulfur; wherein the combination of atoms in —(L)— are selected from thegroup consisting of (i) carbon and hydrogen only, (ii) sulfur only,(iii) oxygen only, (iv) nitrogen and hydrogen only, (v) carbon,hydrogen, and sulfur only, and (vi) and carbon, hydrogen, and oxygenonly; and where R₈₀ is a group selected from (a) or (b);

R₂ is hydrogen, or a group containing 1 to 4 non-hydrogen atoms plus anyrequired hydrogen atoms;

R₃ is —(L₃)—Z, where —(L₃)— is a divalent linker group selected from abond or a divalent group selected from:

and Z is selected from an oxime amide or oxime thioamide grouprepresented by the formulae,

wherein X is oxygen or sulfur, R_(a) is independently selected fromhydrogen, C₁-C₈ alkyl, aryl, C₁-C₈ alkaryl, C₁-C₈ alkoxy, aralkyl and—CN;

R₄ is the group, —(L_(h))-(hydroxyfunctional amide group); wherein—(L_(h))—, is an hydroxyfunctional amide linker having anhydroxyfunctional amide linker length of 1 to 8; and wherein ahydroxyfunctional amide is represented by the formula:

 wherein Y is oxygen, nitrogen (substituted with hydrogen or alkyl) orsulfur;

R^(4a) is selected from the group consisting of OH, (C₁-C₆)alkoxy,(C₇-C₁₄)alkaryloxy, (C₂-C₈)alkenyloxy, (C₇-C₁₄)aralkyloxy,(C₇-C₁₄)aralkenyloxy and aryloxy; and wherein R^(4b) is hydrogen or anorganic substituent selected from the group consisting of C₁-C₈ alkyl,aryl, C₇-C₁₄ aralkyl, C₇-C14 alkaryl, C₃-C₈ cycloalkyl, C₁-C₈alkoxyalkyl and these groups substituted with halogen, —CF₃, —OH, C₁-C₈alkyl, amino, carbonyl, and —CN;

R₅ is selected from hydrogen, a non-interfering substituent, or thegroup, —(L_(a))-(acidic group); wherein —(L_(a))—, is an acid linkerhaving an acid linker length of 1 to 8.

R₆ and R₇ are selected from hydrogen, non-interfering substituent,carbocyclic radical, carbocyclic radical substituted withnon-interfering substituent(s), heterocyclic radicals, and heterocyclicradical substituted with non-interfering substituent(s).

Preferred Subgroups of Compounds of Formula (I)

Preferred R₁ Substituents:

A preferred subclass of compounds of formula (I) are those where for R₁the divalent linking group —(L₁)— is a group represented by any one ofthe following formulae (Ia), (Ib), (Ic), (Id), (Ie), or (If):

where Q₁ is a bond or any of the divalent groups (Ia), (Ib), (Ic), (Id),(Ie), and (If) and each R₁₀ is independently hydrogen, C₁₋₈ alkyl, aryl,C₁₋₈ haloalkyl or C₁₋₈ alkoxy.

Particularly preferred as the linking group —(L₁)— of R₁ is an alkylenechain of 1 or 2 carbon atoms, namely, —(CH₂)— or —(CH₂—CH₂)—.

Also preferred as a subclass of compounds of formula (I) are those whereR₁ is represented by the group —L₁—R₁₁. The preferred group for R₁₁ is asubstituted or unsubstituted group selected from the group consisting ofC₅-C₁₄ cycloalkyl, C₅-C₁₄ cycloalkenyl, phenyl, naphthyl, norbornanyl,bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl,diphenylethylenyl, phenylcyclohexenyl, acenaphthylenyl, and anthracenyl,biphenyl, bibenzylyl and related bibenzylyl homologues represented bythe formula (a);

where n is a number from 1 to 8.

Particularly preferred are compounds of formula (I) wherein for R₁ thecombined group —(L₁)—R₁₁ is selected from the group consisting of

where R₁₂ is a radical independently selected from halo, C₁-C₈ alkyl,C₁-C₈ alkoxy, —S—(C₁-C₈ alkyl), —O—(C₁-C₈ alkyl) and C₁-C₈ haloalkylwhere t is a number from 0 to 5 and u is a number from 0 to 4.

Preferred is the group —(L₁)—R₁₁; where, —(L₁)— is a divalent linkinggroup of 1 to 8 atoms and where R₁₁ is a group selected from (a) or (b).

Preferred for R₁₁ is —(CH₂)_(m)—R¹² wherein m is an integer from 1 to 6,and R¹² is (d) a group represented by the formula:

wherein a, c, e, n, q, and t are independently an integer from 0 to 2,R¹³ and R¹⁴ are independently selected from a halogen, C₁ to C₈ alkyl,C₁ to C₈ alkyloxy, C₁ to C₈ alkylthio, aryl, heteroaryl, and C₁ to C₈haloalkyl, α is an oxygen atom or a sulfur atom, L⁵ is a bond, —(CH₂)v-,—C═C—, —CC—, —O—, or —S—, v is an integer from 0 to 2, β is —CH₂— or—(CH₂)₂—, γ is an oxygen atom or a sulfur atom, b is an integer from 0to 3, d is an integer from 0 to 4, f, p, and w are independently aninteger from 0 to 5, r is an integer from 0 to 7, and u is an integerfrom 0 to 4, or is (e) a member of (d) substituted with at least onesubstituent selected from the group consisting of C₁ to C₆ alkyl, C₁ toC₈ alkyloxy, C₁ to C₈ haloalkyloxy, C₁ to C₈ haloalkyl, aryl, and ahalogen.

Preferred R₂ Substituents:

R₂ is preferably selected from the group consisting of hydrogen, C₁-C₄alkyl, C₂-C₄ alkenyl, —O—(C₁-C₃ alkyl), —S—(C₁-C₃ alkyl), —C₃-C₄cycloalkyl —CF₃, halo, —NO₂, —CN, —SO₃. Particularly preferred R₂ groupsare selected from hydrogen, methyl, ethyl, propyl, isopropyl,cyclopropyl, —F, —CF₃, —Cl, —Br, or —O—CH₃.

Preferred R₃ Substituents:

A preferred subclass of compounds of formula (I) are those wherein X isoxygen.

Another preferred subclass of compounds of formula (I) are those whereinZ is an oxime amide group.

Also preferred are compounds of formula (I) wherein z is an acetamidegroup represented by the structure

and R^(3a) is hydrogen, methyl or ethyl. For the group R₃ it ispreferred that the linking group —(L₃)— be a bond.

Preferred R₄ Substituents:

Another preferred subclass of compounds of formula (I) are those whereinR₄ is a substituent having an hydroxyfunctional amide linker with anhydroxyfunctional amide linker length of 2 or 3 and thehydroxyfunctional amide linker group, —(L_(h))—, for R₄ is selected froma group represented by the formula;

where Q₂ is selected from the group —(CH₂)—, —O—, —NH—, —C(O)—, and —S—,and each R₄₀ is independently selected from hydrogen, C₁-C₈ alkyl, aryl,C₁-C₈ alkaryl, C₁-C₈ alkoxy, aralkyl, and halo. Most preferred arecompounds where the hydroxyfunctional amide linker, —(L_(h))—, for R₄ isselected from the specific groups;

where R₄₀ is hydrogen or CC₁-C₈ alkyl.

Preferred as the hydroxyfunctional amide group in the group R₄ is thegroup:

wherein R^(4a) is selected from the group consisting of OH,(C₁-C₆)alkoxy, (C₂-C₈)alkenyloxy, (C₇-C₁₄)aralkyloxy, and aryloxy; and

wherein R^(4b) is an organic substituent selected from the groupconsisting of H, C₁-C₈ alkyl, aryl, C₇-C₁₄ aralkyl, C₇—C₁₄ alkaryl,C₃-C₈ cycloalkyl, C₁-C₈ alkoxyalkyl and these groups substituted withhalogen, —CF₃, —OH, C₁-C₈ alkyl, amino, carbonyl, and —CN. A morepreferred R^(4a) group is selected from the group consisting of —OH,—OCH₃, phenyloxy and —OC₂H₅ while a more preferred R^(4b) is selectedfrom the group consisting of H, C₁-C₈ alkyl, aryl, C₇-C₁₄ aralkyl,C₇-C₁₄ alkaryl, C₃-C₈ cycloalkyl. A most preferred R4b is a groupselected from H, CH₃, C₂H₅ and C₃H₇. A salt or a prodrug derivative ofthe (hydroxyfunctional amide group) is also a suitable substituent.

Preferred R₅ Substituents:

Preferred acid linker, —(L_(a))—, for R₅ is selected from the groupconsisting of;

wherein R₅₄, R₅₅, R₅₆ and R₅₇ are each independently hydrogen, C₁-C₈alkyl, C₁-C₈ haloalkyl, aryl, C₁-C₈ alkoxy, or halo. Preferred (acidicgroup) for R₅ is selected from the group consisting of —CO₂H, —SO₃H and—P(O)(OH)₂.

Preferred R₆ and R₇ Substituents:

Another preferred subclass of compounds of formula (I) are those whereinfor R₆ and R₇ the non-interfering substituent is independently methyl,ethyl, propyl, isopropyl, thiomethyl, —O-methyl, C₄-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₇-C₁₂ aralkyl, C₇-C₁₂ alkaryl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl,C₁-C₆ alkoxy, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₁₂ alkoxyalkyl,C₂-C₁₂ alkoxyalkyloxy, C₂-C₁₂ alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino,C₂-C₁₂ alkoxyamino, C₂-C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁-C₆alkylthio, C₂-C₁₂ alkylthiocarbonyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₂-C₆ haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆haloalkyl, C₁-C₆ hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O—(C₁-C₆alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO₂R), —CHO, amino,amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro,cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino,hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO₃H,thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8.

Most preferred as non-interfering substituents are methyl, ethyl,propyl, and isopropyl.

Preferred compounds of the invention are those having the generalformula (II), or a pharmaceutically acceptable salt, solvate or prodrugderivative thereof;

wherein

R₂₂ is selected from hydrogen, methyl, ethyl, propyl, isopropyl,cyclopropyl, —F, —CF₃, —Cl, —Br, or —O—CH₃; wherein R^(4a) isindependently selected from the group consisting of OH, (C₁-C₁₀)alkoxy,(C₇-C₁₄)aralkyloxy, (C₂-C₈)alkenyloxy, (C₇-C₁₄) aralkenyloxy,(C₃-C₁₀)cycloalkyloxy, heteroaryloxy and aryl; and wherein R^(4b) isindependently selected from the group consisting of H, C₁-C₈ alkyl,aryl, C₇-C₁₄ aralkyl, C₇-C₁₄ alkaryl, C₃-C₈ cycloalkyl. A preferredR^(4a) group is the group OH, or OCH₃ or phenyloxy; a preferred R^(4b)group is the group H, or (C₁-C₆)alkyl; and —(L_(h))— is a divalent groupselected from;

 where R₄₀, R₄₁, R₄₂, and R₄₃ are each independently selected fromhydrogen or C₁-C₈ alkyl.

R₁₆ is selected from hydrogen, C₁-C₈ alkyl, C₁-C₈ alkoxy, C₁-C₈alkylthio, C₁-C₈ haloalkyl, C₁-C₈ hydroxyalkyl, aryl, heteroaryl andhalo.

R₁₃ is selected from hydrogen and C₁-C₈ alkyl, C₁-C₈ alkoxy, —S—(C₁-C₈alkyl), C₁-C₈ haloalkyl, C₁-C₈, phenyl, halophenyl, hydroxyalkyl, andhalo, and t is an integer from 0 to 5.

Preferred specific compounds (and all pharmaceutically acceptable salts,solvates and prodrug derivatives thereof) which are illustrative of thecompounds of the invention are as follow:

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(hydroxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(methyloxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(methyl)-N-(methyloxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(hydroxy)-N-(methyl)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(ethyloxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(2-propenyloxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(hydroxy)-N-(2-propyl)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(tert-butyloxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-[2-(methyl)propyloxy]acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(phenylmethyloxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(methyl)-N-(phenylmethyloxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(phenyloxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(methyl)-N-(phenyloxy)acetamide;

2-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(cyclohexyl)-N-(hydroxy)acetamide;

2-[[3-(2-Amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(hydroxy)acetamide.

The salts of the above indole compounds represented by formulae (I) and(II) are an additional aspect of the invention. In those instances wherethe compounds of the invention possess acidic or basic functional groupsvarious salts may be formed which are more water soluble andphysiologically suitable than the parent compound. Representativepharmaceutically acceptable salts, include but are not limited to, thealkali and alkaline earth salts such as lithium, sodium, potassium,calcium, magnesium, aluminum and the like. Salts are convenientlyprepared from the free acid by treating the acid in solution with a baseor by exposing the acid to an ion exchange resin.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofcompounds of the present invention, for example, ammonium, quaternaryammonium, and amine cations, derived from nitrogenous bases ofsufficient basicity to form salts with the compounds of this invention(see, for example, S. M. Berge, et al., “Pharmaceutical Salts,” J. Phar.Sci., 66: 1-19 (1977)). Moreover, the basic group(s) of the compound ofthe invention may be reacted with suitable organic or inorganic acids toform salts such as acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride,clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate,fluoride, fumarate, gluceptate, gluconate, glutamate,glycolylarsanilate, hexylresorcinate, bromide, chloride,hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate,malate, malseate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate,pantothenate, phosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate,trifluoromethane sulfonate, and valerate.

Certain compounds of the invention may possess one or more chiralcenters and may thus exist in optically active forms. Likewise, when thecompounds contain an alkenyl or alkenylene group there exists thepossibility of cis- and trans-isomeric forms of the compounds. The R-and S-isomers and mixtures thereof, including racemic mixtures as wellas mixtures of cis- and trans-isomers, are contemplated by thisinvention. Additional asymmetric carbon atoms can be present in asubstituent group such as an alkyl group. All such isomers as well asthe mixtures thereof are intended to be included in the invention. If aparticular stereoisomer is desired, it can be prepared by methods wellknown in the art by using stereospecific reactions with startingmaterials which contain the asymmetric centers and are already resolvedor, alternatively by methods which lead to mixtures of the stereoisomersand subsequent resolution by known methods. For example, a racemicmixture may be reacted with a single enantiomer of some other compound.This changes the racemic form into a mixture of diastereomers anddiastereomers, because they have different melting points, differentboiling points, and different solubilities can be separated byconventional means, such as crystallization.

Prodrugs are derivatives of the compounds of the invention which havechemically or metabolically cleavable groups and become by solvolysis orunder physiological conditions the compounds of the invention which arepharmaceutically active in vivo. Derivatives of the compounds of thisinvention have activity in both their acid and base derivative forms,but the acid derivative form often offers advantages of solubility,tissue compatibility, or delayed release in a mammalian organism (see,Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam1985). Prodrugs include acid derivatives well known to practitioners ofthe art, such as, for example, esters prepared by reaction of the parentacidic compound with a suitable alcohol, or amides prepared by reactionof the parent acid compound with a suitable amine. Simple aliphatic oraromatic esters derived from acidic groups pendent on the compounds ofthis invention are preferred prodrugs. In some cases it is desirable toprepare double ester type prodrugs such as (acyloxy) alkyl esters or((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters asprodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,tert-butyl, morpholinoethyl, and N,N-diethylglycolamido.

N,N-diethylglycolamido ester prodrugs may be prepared by reaction of thesodium salt of a compound of Formula (I) (in a medium such asdimethylformamide) with 2-chloro-N,N-diethylacetamide (available fromAldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).

Morpholinylethyl ester prodrugs may be prepared by reaction of thesodium salt of a compound of Formula (I) (in a medium such asdimethylformamide) 4-(2-chloroethyl)morpholine hydrochloride (availablefrom Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).

a) The 1H-indole-3-glyoxylamide hydroxyfunctional amide derivativecompounds of the invention are prepared from the methyl ester compound1A which was prepared as disclosed in U.S. Pat. No. 5.654,326; theentire contents of which is incorporated herein by reference, and alsoas disclosed in preparation 1, in the experimental section infra.Derivatives of the ester compound of formula (1A) such as thesaponifaction product may also be employed as starting material for thepreparation of compounds of the present invention by those skilled inthe art. In the protocol beginning with compound 1A, the ester isconverted to the hydroxyfunctional amide compound of formula I (seescheme 1 below)

This is accomplished by in-situ cleavage of the ester compound (1A),followed by coupling of the resulting intermediate with a protected orunprotected, substituted or unsubstituted hydroxylamine group orderivative in the presence of a coupling agent to form a protected orunprotected hydroxyfunctional amide derivative of a compound of formula(I). For example, the ester compound of formula (1A) is reacted atambient temperature, in the presence of excess 2,4,6-collidine(collidine) and benzotriazol-1-yolxytris(dimethylamino)phosphoniumhexafluorophosphonate (coupling catalyst, see Tetrahedron Lett, 1219(1975)) with o-(tert-butyldimethylsilyl) hydroxylamine to form after 1-4hours, the o-(tert-butyldimethylsilyl) substituted hydroxyfunctionalamide derivative. The silyl or other protecting group is removed by wellknown methods such as the use of trifluoroacetic acid to afford thedesired hydroxyfunctional amide compound of formula (I).

Typically, the condensation or coupling is performed in a solvent such adimethyl formamide, tetrahydrofuran or aqueous mixtures of the like. Ingeneral protic solvents are preferred for the purpose of this invention.The reaction is catalyzed by a base including weak organic or inorganicbases. Organic bases such as collidine are preferred. The reaction isalso preferably run in the presence of agents that retard or reduceracemization of the hydroxyfunctional amide, the substitutedhydroxylamine or its derivative, such as for example,benzotriazolyl-N-oxy-tris(dimethylamino)phosphonium hexafluorophosphate.

Upon completion of the reaction, the mixture is concentrated in vacuo.The resulting product mixture is chromatographed or crystallized, e.g.,by sonication to obtain the target compound.

It is known to one skilled in the art that numerous coupling proceduresfor example, acid to amide or ester to amide conversion procedures,using various bases and or coupling agents may be practiced to preparethe compounds of the present invention. Scheme 2 below,

provides an alternative scheme for the preparation of compounds of thepresent invention.

Yet another alternative preparation method is the interconversion ofcompounds of the invention as shown for example in Scheme 3:

These and other methods are well known in the arts and can be found inreference texts such as for example J. March Advanced Organic Chemistry,Wiley Interscience publishers, New York, N.Y., 1985, and R. C. LarockComprehensive Organic Transformations, VCH Publishers, New York, N.Y.,1989. The protected compounds of formula (2) are also useful sPLA₂inhibitors and are also compounds of this invention.

b) 1-indole-3-acetamide amino acid derivative sPLA₂ inhibitors aresimilarly prepared by condensation of the protected or unprotected,substituted or unsubstituted hydroxylamine or derivative thereof, withthe 1H-indole-3-acetamide sPLA₂ inhibitor. The 1H-indole-3-acetamidesPLA₂ inhibitors and methods of making them are set out in U.S. Pat. No.5,684,034, the entire disclosure of which is incorporated herein byreference. Indole-3-acetamide hydroxyfunctional amide derivative sPLA₂inhibitor compounds of the present invention are represented bycompounds of formula (IIb), and pharmaceutically acceptable salts andprodrug derivatives thereof,

wherein;

X is oxygen or sulfur;

R₁₁ is selected from groups (i), (ii) (iii) and (iv) where;

(i) is C₆-C₂₀ alkyl, C₆-C₂₀ alkynyl, C₆-C₂₀ alkynyl, C₆-C₂₀ haloalkyl,C₄-C₁₂ cycloalkyl, or

(ii) is aryl or aryl substituted by halo, nitro, —CN, —CHO, —OH, —SH,C₁-C₁₀ alkyl, C₁-C₁₀ alkylthio, C₁-C₁₀ alkoxyl, carboxyl, amino, orhydroxyamino; or

(iii) is —(CH₂)_(n)—(R₈₀), or —(NH)—(R₈₁), where n is 1 to 8, and R₈₀ isa group recited in (i), and R₈₁ is selected from a group recited in (i)or (ii);

(iv) is

where R₈₇ is hydrogen or C₁-C₁₀ alkyl, and R₈₈ is selected from thegroup; phenyl, naphthyl, indenyl, and biphenyl, unsubstituted orsubstituted by halo, —CN, —CHO, —OH, —SH, C₁-C₁₀ alkylthio, C₁-C₁₀alkoxyl, phenyl, nitro, C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, carboxyl, amino,hydroxyamino; or a substituted or unsubstituted 5 to 8 memberedheterocyclic ring;

R₁₂ is halo, C₁-C₆ alkyl, C₁-C₆ alkylthio, or C₁-C₆ alkoxy;

each R₁₃ is independently hydrogen, halo, or methyl;

R₁₄ is the group, —(L_(h))-(hydroxyfunctional amide); wherein —(L_(h))—,is an hydroxyfunctional amide linker having an hydroxyfunctional amidelinker length of 1 to 8; and wherein a hydroxyfunctional amide isrepresented by the formula:

wherein Y is oxygen or sulfur;

R^(14a) selected from the group consisting of OH, (C₁-C₆)alkoxy,(C₇-C₁₄)alkaryloxy, (C₂-C₈)alkenyloxy, (C₂-C₈)alkynyloxy, (C₇-C₁₄)aralkyloxy, (C₇-C₁₄)aralkenyloxy and aryloxy; and

wherein R^(14b) is hydrogen or an organic substituent selected from thegroup consisting of C₁-C₈ alkyl, aryl, C₇-C₁₄ aralkyl, C₇-C₁₄ alkaryl,C₃-C₈ cycloalkyl, C₁-C₈ alkoxyalkyl and these groups substituted withhalogen, —CF₃, —OH, C₁-C₈ alkyl, amino, carbonyl, and —CN;

R₁₅, R₁₆, and R₁₇ are each independently hydrogen, C₁—C₁₀ alkyl, C₁-C₁₀alkenyl, C₁-C₁₀ alkynyl, C₃-C₈ cycloalkyl, aryl, aralkyl, or any twoadjacent hydrocarbyl groups in the set R₁₅, R₁₆, and R₁₇, combine withthe ring carbon atoms to which they are attached to form a 5 or 6membered substituted or unsubstituted carbocyclic ring; or C₁-C₁₀haloalkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ haloalkoxy, C₄-C₈ cycloalkoxy, phenoxy,halo, hydroxy, carboxyl, —SH, —CN, C₁-C₁₀ alkylthio, arylthio,thioacetal, —C(O)O(CC₁-C₁₀ alkyl), hydrazide, hydrazino, hydrazido,—NH₂, —NO₂, —NR₈₂R₈₃, and —C(O)NR₈₂R₈₃, where, R₈₂ and R₈₃ areindependently hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ hydroxyalkyl, or takentogether with N, R₈₂ and R₈₃ form a 5- to 8-membered heterocyclic ring;or a group having the formula;

where,

R₈₄ and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl,hydroxy, or R₈₄ and R₈₅ taken together are ═O;

p is 1 to 5,

Z is a bond, —O—, —N(C₁-C₁₀ alkyl)-, —NH—, or —S—; and

Q is —CON(R₈₂R₈₃), -5-tetrazolyl, —SO₃H,

 where f is 1 to 8, R₈₆ is independently selected from hydrogen, ametal, or C₁-C₁₀ alkyl, and R₉₉ is selected from hydrogen or C₁-C₁₀alkyl.

c) Indole-3-Oxime amide compounds of the invention are represented bycompounds of formula (III) or a pharmaceutically acceptable salt,solvate or prodrug thereof;

wherein

R₁ is selected from groups (a), (b), and (c) wherein;

(a) is C₇-C₂₀ alkyl, C₇-C₂₀ haloalkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl,carbocyclic radical, or heterocyclic radical, or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents; or

(c) is the group —(L₁)—R₁₁; where, —(L₁)— is a divalent linking group of1 to 8 atoms and where R₁₁ is a group selected from (a) or (b);

R₂ is hydrogen, or a group containing 1 to 4 non-hydrogen atoms plus anyrequired hydrogen atoms;

—(L₃)—Z, is the group where —(L₃)— is a divalent linker group selectedfrom a bond or a divalent group selected from:

and Z is selected from an oxime amide or oxime thioamide grouprepresented by the formulae,

wherein, X is oxygen or sulfur; and R_(a) is selected from hydrogen,C₁-C₈ alkyl, aryl, C₁-C₈ alkaryl, C₁-C₈ alkoxy, aralkyl and —CN;

R₄ is the group, —(L_(h))-(hydroxyfunctional amide); wherein —(L_(h))—,is an hydroxyfunctional amide linker having an hydroxyfunctional amidelinker length of 1 to 8;

R₅ is selected from hydrogen, a non-interfering substituent, or thegroup, —(L_(a))-(acidic group); wherein —(L_(a))—, is an acid linkerhaving an acid linker length of 1 to 8.

R₆ and R₇ are selected from hydrogen, non-interfering substituent,carbocyclic radical, carbocyclic radical substituted withnon-interfering substituent(s), heterocyclic radicals, and heterocyclicradical substituted with non-interfering substituent(s).

Preferred Subgroups of Compounds of Formula (III)

Preferred R₁ Substituents:

A preferred subclass of compounds of formula (III) are those where forR₁ the divalent linking group —(L₁)— is a group represented by any oneof the following formulae (Ia), (Ib), (Ic), (Id), (Ie), or (If):

where Q₁ is a bond or any of the divalent groups (Ia), (Ib), (Ic), (Id),(Ie), and (If) and each R₁₀ is independently hydrogen, C₁-C₈ alkyl,C₁-C₈ haloalkyl or C₁-C₈ alkoxy.

Particularly preferred as the linking group —(L₁)— of R₁ is an alkylenechain of 1 or 2 carbon atoms, namely, —(CH₂)— or —(CH₂—CH₂)—.

The preferred group for R₁₁ is a substituted or unsubstituted groupselected from the group consisting of C₅-C₁₄ cycloalkyl, C₅-C₁₄cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl,tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl,phenylcyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl,bibenzylyl and related bibenzylyl homologues represented by the formula(a);

where n is a number from 1 to 8.

Particularly preferred are compounds wherein for R₁ the combined group—(L₁)—R₁₁ is selected from the group consisting of

where R₁₂ is a radical independently selected from halo, C₁-C₈ alkyl,C₁-C₈ alkoxy, —S—(C₁-C₈ alkyl), —O—(C₁-C₈ alkyl) and C₁-C₈ haloalkylwhere t is a number from 0 to 5 and u is a number from 0 to 4.

Also preferred for R₁₁ is —(CH₂)m-R¹² wherein m is an integer from 1 to6, and R¹² is (d) a group represented by the formula:

wherein a, C, e, n, q, and t are independently an integer from 0 to 2,R¹³ and R¹⁴ are independently selected from a halogen, C₁ to C₈ alkyl,C₁ to C₈ alkyloxy, C₁ to C₈ alkylthio, aryl, heteroaryl, and C₁ to C₈haloalkyl, α is an oxygen atom or a sulfur atom, L⁵ is a bond, —(CH₂)v-,—C═C—, —CC—, —O—, or —S—, v is an integer from 0 to 2, β is —CH₂— or—(CH₂)₂—, γ is an oxygen atom or a sulfur atom, b is an integer from 0to 3, d is an integer from 0 to 4, f, p, and w are independently aninteger from 0 to 5, r is an integer from 0 to 7, and u is an integerfrom 0 to 4, or is (e) a member of (d) substituted with at least onesubstituent selected from the group consisting of C₁ to C₆ alkyl, C₁ toC₈ alkyloxy, C₁ to C₈ haloalkyloxy, C₁ to C₈ haloalkyl, aryl, and ahalogen.

Preferred R₂ Substituents:

R₂ is preferably selected from the group consisting of hydrogen, C₁-C₄alkyl, C₂-C₄ alkenyl, —O—(C₁-C₃ alkyl), —S—(C₁-C₃ alkyl), —C₃-C₄cycloalkyl —CF₃, halo, —NO₂, —CN, —SO₃. Particularly preferred R₂ groupsare selected from hydrogen, methyl, ethyl, propyl, isopropyl,cyclopropyl, —F, —CF₃, —Cl, —Br, or —O—CH₃.

Preferred R₄ Substituents:

Another preferred subclass of compounds of formula (III) are thosewherein R₄ is a substituent having an hydroxyfunctional amide linkerwith an hydroxyfunctional amide linker length of 2 or 3 and thehydroxyfunctional amide linker group, —(L_(h))—, for R₄ is selected froma group represented by the formula;

where Q₂ is selected from the group —(CH₂)—, —O—, —NH—, —C(O)—, and —S—,and each R₄₀ is independently selected from hydrogen, C₁-C₈ alkyl, aryl,C₁-C₈ alkaryl, C₁-C₈ alkoxy, aralkyl, and halo. Most preferred arecompounds where the hydroxyfunctional amide linker, —(L_(h))—, for R₄ isselected from the specific groups;

where R₄₀ is hydrogen or C₁-C₈ alkyl.

Preferred as the hydroxyfunctional amide in the group R₄ is the group:

wherein R^(4a) selected from the group consisting of OH, (C₁-C₆)alkoxy,(C₇-C₁₄)alkaryloxy, (C₂-C₈)alkenyloxy, (C₇-C₁₄)aralkyloxy,(C₇-C₁₄)aralkenyloxy and aryloxy; and

wherein R^(4b) is selected from the group consisting of H, (C₁-C₆)alkyl,heteroaryl and aryl. A preferred R^(4a) group is the group —OH. A saltor a prodrug derivative of the (hydroxyfunctional amide group) is also asuitable substituent.

Preferred R₅ Substituents:

Preferred acid linker, —(L_(a))—, for R₅ is selected from the groupconsisting of;

wherein R₅₄, R₅₅, R₅₆ and R₅₇ are each independently hydrogen, C₁-C₈alkyl, C₁-C₈ haloalkyl, aryl, C₁-C₈ alkoxy, or halo. Preferred (acidicgroup) for R₅ is selected from the group consisting of —CO₂H, —SO₃H and—P(O)(OH)₂

Preferred R₆ and R₇ Substituents:

Another preferred subclass of compounds of formula (III) are thosewherein for R₆ and R₇ the non-interfering substituent is independentlymethyl, ethyl, propyl, isopropyl, thiomethyl, —O-methyl, C₄-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₇-C₁₂ aralkyl, C₇-C₁₂ alkaryl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl,C₁-C₆ alkoxy, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₁₂ alkoxyalkyl,C₂-C₁₂ alkoxyalkyloxy, C₂-C₁₂ alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino,C₂-C₁₂ alkoxyamino, C₂-C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁-C₆alkylthio, C₂-C₁₂ alkylthiocarbonyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₂-C₆ haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆haloalkyl, C₁-C₆ hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O—(C₁-C₆alkyl), benzyloxy, phenoxy, phenylthio, —(CONHSO₂R), —CHO, amino,amidino, bromo, carbamyl, carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro,cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino,hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO₃H,thioacetal, thiocarbonyl, and carbonyl; where n is from 1 to 8.

Most preferred as non-interfering substituents are methyl, ethyl,propyl, and isopropyl.

The indole-3-oxime compounds of the invention can be prepared followingprotocol of scheme 4 below;

To introduce the oxime functionality, the methyl ester of theglyoxylamide (compound 10 in scheme 1, compound 1 in scheme 2, supra.)is heated with hydroxylamine hydrochloride (when R is H) in aTHF/methanol mixture for 8 hours or until the reaction was deemedcomplete. The reaction product is isolated by chromatography or otherknown laboratory procedure to afford a white solid. Substituted oximessuch as when R is methyl, ethyl, phenyl or other substituent can beprepared by reacting the corresponding substituted hydroxylaminehydrochloride or free base with the glyoxylamide as described supra. Theester functionality at the 4 or 5 position on the indole nucleus, as infor example, compound 2, can be: (a) converted to the acid by hydrolysisusing lithium hydroxide or other known ester hydrolysis methods toafford compounds of formula 3, or (b) converted to an hydroxyfunctionalamide functionality directly or via the acid functionality to affordcompounds of formula 4. Preparation of the hydroxyfunctional amidederivative from the ester or acid derivative (Scheme 4, compound 2 or 3respectively) have also been disclosed supra for the glyoxylamidecompounds of formula I.

General procedures for the conversion of organic acids to amides andamide derivatives (e.g., hydroxyfunctional amides) are well known toartisans in the field, and have been documented in general referencetexts including for example , J. March Advanced Organic Chemistry, WileyInterscience publishers, New York, N.Y., 1985, and R. C. Larock,Comprehensive Organic Transformations, VCH Publishers, New York, N.Y.,1989. Additional references, or procedures are found in J. Jones AminoAcids and Peptide Synthesis, Oxford Science Publications, Stephen G.Davis, Editor, Oxford University Press Inc., New York, N.Y., 1992.

III. Method of Making the 1H-Indole-3-Glyoxyamide Starting Material forPreparing the Compounds of the Invention

The synthesis of the indole compounds of the invention (viz., Compoundsof Formulae I and II) can be accomplished by well known methods asrecorded in the chemical literature. In particular, the indole startingmaterials may be prepared by the synthesis schemes taught in U.S. Pat.No. 5,654,326; the disclosure of which is incorporated herein byreference. Another method of making 1H-indole-3-glyoxylamide sPLA₂inhibitors is described in U.S. patent application Ser. No. 09/105381,filed Jun. 26, 1998 and titled, “Process for Preparing 4-substituted1-H-Indole-3-glyoxyamides” the entire disclosure of which isincorporated herein by reference.

U.S. patent application Ser. No. 09/105381 discloses the followingprocess having steps (a) thru (i): Preparing a compound of the formula(Iz) or a pharmaceutically acceptable salt or prodrug derivative thereof

wherein:

R^(1z) is selected from the group consisting of —C₇-C₂₀ alkyl,

where

R^(10z) is selected from the group consisting of halo, C₁-C₁₀ alkyl,C₁-C₁₀ alkoxy, —S—(C₁-C₁₀ alkyl) and halo(C₁-C₁₀)alkyl, and tz is aninteger from 0 to 5 both inclusive;

R^(2z) is selected from the group consisting of hydrogen, halo, C₁-C₃alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl, —O—(C₁-C₂ alkyl), —S—(C₁-C₂alkyl), aryl, aryloxy and HET;

R^(4z) is the group —CO₂H, or salt and prodrug derivative thereof; and

R^(5z), R^(6z) and R^(7z) are each independently selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo (C₁-C₆)alkoxy,halo(C₂-C₆)alkyl, bromo, chloro, fluoro, iodo and aryl;

which process comprises the steps of:

a) halogenating a compound of formula Xz

 where R^(8z) is (C₁-C₆)alkyl, aryl or HET; with SO₂Cl₂ to form acompound of formula IX

b) hydrolyzing and decarboxylating a compound of formula IXz

 to form a compound of formula VIIIz

c) alkylating a compound of formula VIIz

 with a compound of formula VIIIz

 to form a compound of formula VIz

d) aminating and dehydrating a compound of formula VIz

 with an amine of the formula R^(1z)NH₂ in the presence of a solventthat forms and azeotrope with water to form a compound of formula Vz;

e) oxidizing a compound of formula Vz

 by refluxing in a polar hydrocarbon solvent having a boiling point ofat least 150° C. and a dielectric constant of at least 10 in thepresence of a catalyst to form a compound of formula IVz

f) alkylating a compound of the formula IVz

 with an alkylating agent of the formula XCH₂R^(4az) where X is aleaving group and R^(4az) is —CO₂R^(4b), where R^(4bz) is an acidprotecting group to form a compound of formula IIIz

g) reacting a compound of formula IIIz

 with oxalyl chloride and ammonia to form a compound of formula IIz

h) optionally hydrolyzing a compound of formula IIz

 to form a compound of formula Iz.

An alternative protocol useful for the synthesis of the startingmaterial is shown in Scheme 6 below:

The synthesis of indole-3-oxime amides (compound of formula I and II,supra.) of this invention uses as starting material the glyoxamide((3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)aceticacid methyl ester, compound 10, supra. This starting material isprepared as set out in the preceding section or by the method of Example9 of U.S. Pat. No. 5,654,326 (the disclosure of which is incorporatedherein by reference).

To obtain the glyoxylamide starting material substituted in the4-position with an (acidic group) linked through an oxygen atom, thereactions outlined in the scheme supra, are used (for conversions 1through 5, see ref. Robin D. Clark, Joseph M. Muchowski, Lawrence E.Fisher, Lee A. Flippin, David B. Repke, Michel Souchet, Synthesis, 1991,871-878, the disclosures of which are incorporated herein by reference).The starting material ortho-nitrotoluene, 1, is readily reduced to2-methyl,3-methoxyaniline, 2. Reduction of 1 is by the catalytichydrogenation of the corresponding nitrotoluene using palladium oncarbon as catalyst. The reduction can be carried out in ethanol ortetrahydrofuran (THF) or a combination of both, using a low pressure ofhydrogen. The aniline 2, obtained, is converted to theN-tert-butyloxycarbonyl derivative 3, in good yield, on heating withdi-tert-butyl dicarbonate in THF at reflux temperature. The dilithiumsalt of the dianion of 3 is generated at −40 to −20° C. in THF usingsec-butyllithium and reacted with the appropriately substitutedN-methoxy-N-methylalkanamide to form the ketone 4. This product (4) maybe purified by crystallization from hexane, or reacted directly withtrifluoroacetic acid in methylene chloride to give the 1,3-unsubstitutedindole 5. The 1,3-unsubstituted indole 5 is reacted with sodium hydridein dimethylformamide at room temperature (20-25° C.) for 0.5-1.0 hour.The resulting sodium salt of 5 is treated with an equivalent ofarylmethyl halide and the mixture stirred at a temperature range of0-100° C., usually at ambient room temperature, for a period of 4 to 36hours to give the 1-arylmethylindole, 6. This indole, 6, isO-demethylated by stirring with boron tribromide in methylene chloridefor approximately 5 hours (see ref. Tsung-Ying Shem and Charles AWinter, Adv. Drug Res., 1977, 12, 176, the disclosure of which isincorporated herein by reference). The 4-hydroxyindole, 7, is alkylatedwith an alpha bromoalkanoic acid ester in dimethylformamide (DMF) usingsodiumhydride as a base, with reaction condition of 5 to 6. Theα-[(indol-4-yl)oxy]alkanoic acid ester, 8, is reacted with oxalylchloride in methylene chloride to give 9, which is not purified butreacted directly with ammonia to give the glyoxamide 10.

Glyoxamide starting material compounds substituted at the 5 position ofthe indole nucleus with an (acidic group) may be prepared by methods andstarting materials shown in schemes 2 an d 3 of U.S. Pat. No. 5,654,326;the disclosure of which is incorporated herein by reference.

IV. Methods of Using the Compounds of the Invention

The indole compounds described herein are believed to achieve theirbeneficial therapeutic action principally by direct inhibition ofmammalian (including human) sPLA₂, and not by acting as antagonists forarachidonic acid, nor other active agents below arachidonic acid in thearachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, andetc.

The method of the invention for inhibiting sPLA₂ mediated release offatty acids comprises contacting mammalian sPLA₂ with a therapeuticallyeffective amount of indole compounds corresponding to Formulae (I) or(II) as described herein including salt or a prodrug derivative thereof.

Another aspect of this invention is a method for treating InflammatoryDiseases such as inflammatory bowel disease, septic shock, adultrespiratory distress syndrome, pancreatitis, trauma, bronchial asthma,allergic rhinitis, rheumatoid arthritis, osteoarthritis, and relateddiseases which comprises administering to a mammal (including a human) atherapeutically effective dose of the indole compound of the invention(see, formulae I and II).

As previously noted the compounds of this invention are useful forinhibiting sPLA₂ mediated release of fatty acids such as arachidonicacid. By the term, “inhibiting” is meant the prevention ortherapeutically significant reduction in release of sPLA₂ initiatedfatty acids by the compounds of the invention. By “pharmaceuticallyacceptable” it is meant the carrier, diluent or excipient must becompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The specific dose of a compound administered according to this inventionto obtain therapeutic or prophylactic effects will, of course, bedetermined by the particular circumstances surrounding the case,including, for example, the compound administered, the route ofadministration and the condition being treated. Typical daily doses willcontain a non-toxic dosage level of from about 0.01 mg/kg to about 50mg/kg of body weight of an active compound of this invention.

Preferably compounds of the invention (per Formula I or II) orpharmaceutical formulations containing these compounds are in unitdosage form for administration to a mammal. The unit dosage form can bea capsule or tablet itself, or the appropriate number of any of these.The quantity of Active ingredient in a unit dose of composition may bevaried or adjusted from about 0.1 to about 1000 milligrams or moreaccording to the particular treatment involved. It may be appreciatedthat it may be necessary to make routine variations to the dosagedepending on the age and condition of the patient. The dosage will alsodepend on the route of administration.

The compound can be administered by a variety of routes including oral,aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular,and intranasal.

Pharmaceutical formulations of the invention are prepared by combining(e.g., mixing) a therapeutically effective amount of the indole compoundof the invention together with a pharmaceutically acceptable carrier ordiluent therefor. The present pharmaceutical formulations are preparedby known procedures using well known and readily available ingredients.

In making the compositions of the present invention, the Activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semi-solid or liquid material which acts asa vehicle, or can be in the form of tablets, pills, powders, lozenges,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), or ointment, containing, for example, up to 10%by weight of the active compound. The compounds of the present inventionare preferably formulated prior to administration.

For the pharmaceutical formulations any suitable carrier known in theart can be used. In such a formulation, the carrier may be a solid,liquid, or mixture of a solid and a liquid. For example, for intravenousinjection the compounds of the invention may be dissolved in at aconcentration of 2 mg/ml in a 4% dextrose/0.5% Na citrate aqueoussolution. Solid form formulations include powders, tablets and capsules.A solid carrier can be one or more substances which may also act asflavoring agents, lubricants, solubilisers, suspending agents, binders,tablet disintegrating agents and encapsulating material.

Tablets for oral administration may contain suitable excipients such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate,together with disintegrating agents, such as maize, starch, or alginicacid, and/or binding agents, for example, gelatin or acacia, andlubricating agents such as magnesium stearate, stearic acid, or talc.

In powders the carrier is a finely divided solid which is in admixturewith the finely divided Active ingredient. In tablets the Activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. The powders and tablets preferably contain from about 1 toabout 99 weight percent of the Active ingredient which is the novelcompound of this invention. Suitable solid carriers are magnesiumcarbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin,starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, low melting waxes, and cocoa butter.

Sterile liquid form formulations include suspensions, emulsions, syrupsand elixirs.

The Active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent or a mixture of both. The Active ingredient can often bedissolved in a suitable organic solvent, for instance aqueous propyleneglycol. Other compositions can be made by dispersing the finely dividedActive ingredient in aqueous starch or sodium carboxymethyl cellulosesolution or in a suitable oil.

The following pharmaceutical formulations 1 thru 8 are illustrative onlyand are not intended to limit the scope of the invention in any way.“Active ingredient”, refers to a compound according to Formula (I) or(II) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

FORMULATION 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

FORMULATION 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665 mg

The components are blended and compressed to form tablets each weighing665 mg

FORMULATION 3

An aerosol solution is prepared containing the following components:

Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22(Chlorodifluoromethane) 74.00 Total 100.00

The active compound is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

FORMULATION 4

Tablets, each containing 60 mg of Active ingredient, are made asfollows:

Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mgPolyvinylpyrrolidone (as 10% solution in water) 4 mg Sodiumcarboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total150 mg

The Active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

FORMULATION 5

Capsules, each containing 80 mg of Active ingredient, are made asfollows:

Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mgMagnesium stearate 2 mg Total 200 mg

The Active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

FORMULATION 6

Suppositories, each containing 225 mg of Active ingredient, are made asfollows:

Active ingredient 225 mg Saturated fatty acid glycerides 2,000 mg Total2,225 mg

The Active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

FORMULATION 7

Suspensions, each containing 50 mg of Active ingredient per 5 ml dose,are made as follows:

Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified waterto total 5 ml

The Active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION 8

An intravenous formulation may be prepared as follows:

Active ingredient 100 mg Isotonic saline 1,000 ml

The solution of the above ingredients generally is administeredintravenously to a subject at a rate of 1 ml per minute.

Assay

The following chromogenic assay procedure was used to identify andevaluate inhibitors of recombinant human secreted phospholipase A₂. Theassay described herein has been adapted for high volume screening using96 well microtiter plates. A general description of this assay method isfound in the article, “Analysis of Human Synovial Fluid Phospholipase A₂on Short Chain Phosphatidylcholine-Mixed Micelles: Development of aSpectrophotometric Assay Suitable for a Microtiterplate Reader”, byLaure J. Reynolds, Lori L. Hughes, and Edward A Dennis, AnalyticalBiochemistry, 204, pp. 190-197, 1992 (the disclosure of which isincorporated herein by reference):

Reagents:

REACTION BUFFER

CaCl₂.2H₂O (1.47 g/L)

KCl (7.455 g/L)

Bovine Serum Albumin (fatty acid free) (1 g/L) (Sigma A-7030, product ofSigma Chemical Co., St. Louis Mo., USA)

TRIS HCl (3.94 g/L)

pH 7.5 (adjust with NaOH)

ENZYME BUFFER

0.05 NaOAc.3H_(2O, pH) 4.5

0.2 NaCl

Adjust pH to 4.5 with acetic acid

DTNB—5,5′-dithiobis-2-nitrobenzoic acid

RACEMIC DIHEPTANOYL THIO—PC

racemic1,2-bis(heptanoylthio)-1,2-dideoxy-sn-glycero-3-phosphorylcholine

TRITON X-100™ prepare at 6.249 mg/ml in reaction buffer to equal 10 μM.

REACTION MIXTURE

A measured volume of racemic dipheptanoyl thio PC supplied in chloroformat a concentration of 100 mg/ml is taken to dryness and redissolved in10 millimolar

TRITON X-100™ nonionic detergent aqueous solution.

Reaction Buffer is added to the solution, then DTNB to give the ReactionMixture.

The reaction mixture thus obtained contains 1 mM diheptanoly thio-PCsubstrate, 0.29 mm Triton X-100™ detergent, and 0.12 mm DTMB in abuffered aqueous solution at pH 7.5.

Assay Procedure:

1. Add 0.2 ml reaction mixture to all wells;

2. Add 10 ul test compound (or solvent blank) to appropriate wells, mix20 seconds;

3. Add 50 nanograms of sPLA₂ (10 microliters) to appropriate wells;

4. Incubate plate at 40° C. for 30 minutes;

5. Read absorbance of wells at 405 nanometers with an automatic platereader.

All compounds were tested in triplicate. Typically, compounds weretested at a final concentration of 5 ug/ml. Compounds were consideredactive when they exhibited 40% inhibition or greater compared touninhibited control reactions when measured at 405 nanometers. Lack ofcolor development at 405 nanometers evidenced inhibition. Compoundsinitially found to be active were reassayed to confirm their activityand, if sufficiently active, IC₅₀ values were determined. Typically, theIC₅₀ values (see, Table I, below) were determined by diluting testcompound serially two-fold such that the final concentration in thereaction ranged from 45 ug/mL to 0.35 ug/ml. More potent inhibitorsrequired significantly greater dilution. In all cases, % inhibitionmeasured at 405 nanometers generated by enzyme reactions containinginhibitors relative to the uninhibited control reactions was determined.Each sample was titrated in triplicate and result values were averagedfor plotting and calculation of IC₅₀ values. IC₅₀ were determined byplotting log concentration versus inhibition values in the range from10-90% inhibition.

Results of Human Secreted Phospholipase A₂ Inhibition Tests

TABLE Compound No. Inhibition of human secreted from PLA₂ IC50 ± meandeviation Examples 1-16 (3-6 tests) (nM) 1 (SM) 49 2Aa 18.7 +− 3   2Ab36.3 +− 10  2Ac 108 +− 25 2Ad  20 +− 10 2Ae 63.7 +− 6.0 2Af 37.3 +− 4.02Ag 39.5 +− 5.0 2Ah  51.8 +− 10.0 2Ai 24.7 +− 7.0 2Aj 24.3 +− 2.0 2Ak15.0 +− 3.0 2Al  9.0 +− 2.0 2Am  37.3 +− 13.0 2An 25.3 +− 5.0 2Ba 23.3+− 3.0 2Bb 22.2 +− 3.0

The compound of formula 1 (starting material) is highly active ininhibiting sPLA₂ and is included in the table above, for purposes ofcomparison only.

While the present invention has been illustrated above by certainspecific embodiments, it is not intended that these specific examplesshould limit the scope of the invention as described in the appendedclaims.

Experimental

All of the products of the Examples described below as well asintermediates used in the following procedures showed satisfactory nmrand IR spectra. They also had the correct mass spectral values.

Preparation 1

Preparation of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid methyl ester, a compound represented by the compound of formula (1)formula:

A) Preparation of 2-Ethyl-4-methoxy-1H-indole.

A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexanewas added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline(21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below −40°C. with a dry ice-ethanol bath. The bath was removed and the temperatureallowed to warm to 0° C. and then the bath replaced. After thetemperature had cooled to −60° C., 18.5 g (0.18 mol) ofN-methoxy-N-methylpropanamide in an equal volume of THF was addeddropwise. The reaction mixture was stirred 5 minutes, the cooling bathremoved and stirred an additional 18 hours. It was then poured into amixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer wasseparated, washed with water, brine, dried over MgSO₄, and concentratedat reduced pressure to give 25.5 g of a crude of1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. Thismaterial was dissolved in 250 mL of methylene chloride and 50 mL oftrifluoroacetic acid and stirred for a total of 17 hours. The mixturewas concentrated at reduced pressure and ethyl acetate and water addedto the remaining oil. The ethyl acetate was separated, washed withbrine, dried (MgSO₄) and concentrated. The residue was chromatographedthree times on silica eluting with 20% EtOAc/hexane to give 13.9 g of2-ethyl-4-methoxy-1H-indole.

Analyses for C₁₁H₁₃NO: Calculated: C, 75.40; H, 7.48; N, 7.99. Found: C,74.41; H, 7.64; N, 7.97.

Preparation of 2-Ethyl-4-methoxy-1-(phenylmethyl)-1H-indole.

2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) was dissolved in 30 mL ofDMF and 960 mg (24 mmol) of 60% NaH/mineral oil was added. After 1.5hours, 2.9 mL(24 mmol) of benzyl bromide was added. After 4 hours, themixture was diluted with water and extracted twice with ethyl acetate.The combined ethyl acetate was washed with brine, dried (MgSO₄) andconcentrated at reduced pressure. The residue was chromatographed onsilica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole.

Preparation of 2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole.

3.1 g (11.7 mmol) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole wasO-demethylated by treating it with 48.6 mL of 1M BBr₃ in methylenechloride with stirring at room temperature for 5 hours, followed byconcentration at reduced pressure. The residue was dissolved in ethylacetate, washed with brine and dried (MgSO₄). After concentrating atreduced pressure, the residue was chromatographed on silica gel elutingwith 20% EtOAc/hexane to give 1.58 g (54% yield) of2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole, mp, 86-90° C.

Analyses for C₁₇H₁₇NO: Calculated: C, 81.24; H, 6.82; N, 5.57. Found: C,81.08; H, 6.92; N, 5.41.

Preparation of [[2-Ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acidmethyl ester.

2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (1.56 g, 6.2 mmol) wasadded to a mixture of 248 mg (6.2 mmol) of 60% NaH/mineral oil in 20 mLDMF and stirred for 0.67 hour.

Then 0.6 mL (6.2 mmol) of methyl bromoacetate was added and stirring wascontinued for 17 hours. The mixture was diluted with water and extractedwith ethyl acetate. The ethyl acetate solution was washed with brine,dried (MgSO₄), and concentrated at reduced pressure. The residue waschromatographed on silica gel eluting with 20% EtOAc/hexane, to give1.37 g (69% yield) of[[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester,89-92° C.

Analyses for C₂₀H₂₁NO₃: Calculated: C, 74.28; H, 6.55; N, 4.33. Found:C, 74.03; H, 6.49; N, 4.60.

Preparation of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid methyl ester.

Oxalyl chloride (0.4 mL, 4.2 mmol) was added to 1.36 g (4.2 mmol) of[[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester in10 mL of methylene chloride and the mixture stirred for 1.5 hours. Themixture was concentrated at reduced pressure and residue taken up in 10mL of methylene chloride. Anhydrous ammonia was bubbled in for 0.25hours, the mixture stirred for 1.5 hours and evaporated at reducedpressure. The residue was stirred with 20 mL of ethyl acetate and themixture filtered. The filtrate was concentrated to give 1.37 g of amixture of[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid methyl ester and ammonium chloride. This mixture melted at 172-187°C.

EXAMPLE 12-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(hydroxy)acetamide

To a stirred suspension of 1A (0.100 g, 0.263 mmol) anhydrous DMF (1 mL)at ambient temperature was added collidine (0.0331 mL, 0.273 mmol),O-(tert-butyldimethylsilyl)hydroxylamine (0.0366 g, 0.249 mmol), andbenzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate(0.115 g, 0.261 mmol) sequentially. After 2 h the reaction mixture wasdiluted with xylenes (15 mL). After sitting for two hours the silylgroup was removed and a light yellow precipitate formed. To thesuspension was added THF (3 mL), then it was sonicated and filtered. Theprecipitate was taken up in THF/H₂O (5 mL/1 mL) and sonicated. To thiswas added Et₂O (5 mL) and it was again sonicated, then filtered andwashed with cold THF to give 2Aa (60.1 mg) as a pale yellow solid in 61%yield. ¹H NMR (DMSO-d₆) δ 1.04 (t, J=7.1 Hz, 3H), 2.89 (br q, J=7.1 Hz,2H), 3.30 (s, 2H), 4.56 (br s, 2H), 6.55 (br d, J=5.1 Hz, 1H), 6.98-7.08(m, 4H), 7.19-7.31 (m, 3H), 7.74 (s, 1H), 8.09 (s, 1H), 8.93 (s, 1H),10.43 (s, 1H); ESIMS m/e 396 (M⁺+1).

EXAMPLE 22-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(methyloxy)acetamide

N-Methylmorpholine (0.100 mL, 0.910 mmol) was added to a stirredsuspension of 1A (0.100 g, 0.263 mmol) and methoxyamine hydrochloride(0.0242 g, 0.289 mmol) in anhydrous DMF (2 mL) at ambient temperature toform a clear solution. Powderedbenzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate(0.140 g, 0.315 mmol) was added to the solution and the mixture wasstirred for 4 h. The reaction mixture was concentrated in vacuo at 37°C. to a 1 mL solution before it was subject to chromatography on silicagel (gradient 0-4% CH₃OH in CH₂Cl₂) to provide 2Ab (105 mg) as a yellowsolid in 98% yield. mp 228° C. (dec.); IR(KBr) 3422, 3188, 1694, 1678,1629 cm⁻¹; ¹H NMR (DMSO-d₆) δ 1.04 (t, J=6.8 Hz, 3H), 2.91 (q, J=6.8 Hz,2H), 3.55 (s, 3H), 4.57 (s, 2H), 5.51 (s, 2H), 6.56-6.59 (m, 1H),6.98-7.09 (m, 4H), 7.21-7.31 (m, 3H), 7.74 (s, 1H), 8.09 (s, 1H), 11.07(s, 1H); ESIMS m/e 410 (M⁺+1).

Elemental Analyses for C₂₂H₂₃N₃O₅: Calculated: C, 64.54; H, 5.66; N,10.26. Found: C, 64.22; H, 5.70; N, 10.38.

EXAMPLE 32-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(methyl)-N-(methyloxy)acetamide

Following the procedure as described in the Example 2, compound 2AC wassynthesized, as a yellow solid in 83% yield, from Ia andN,O-dimethylhydroxylamine hydrochloride. mp 168.0-170.0° C.; IR(KBr)3442, 3225, 1701, 1662, 1630, 1601 cm⁻¹; ¹H NMR (DMSO-d₆) δ 1.04 (t,J=7.3 Hz, 3H), 2.84 (q, J=7.3 Hz, 2H), 3.11 (s, 3H), 3.73 (s, 3H), 4.85(s, 2H), 5.48 (s, 2H), 6.44-6.47 (m, 1H), 6.98-7.04 (m, 4H), 7.21-7.31(m, 3H), 7.35 (s, 1H), 7.69 (s, 1H); ESIMS m/e 424 (M⁺+1).

Elemental Analyses for C₂₃H₂₅N₃O₅: Calculated: C, 65.24; H, 5.95; N,9.92. Found: C, 65.02; H, 5.77; N, 9.92.

EXAMPLE 42-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(hydroxy)-N-(methyl)acetamide

Following the procedure as described in the Example 2, compound 2Ad wassynthesized, as a yellow solid in 30% yield, from 1A andN-methylhydroxylamine hydrochloride. mp 217° C. (dec.); IR(KBr) 3401,3173, 1698, 1676, 1641 cm⁻¹; ¹H NMR (DMSO-d₆) δ 1.04 (t, J=7.0 Hz, 3H),2.86 (q, J=7.0 Hz, 2H), 3.11 (s, 3H), 4.82 (s, 2H), 5.48 (s, 2H), 6.37(s, 1H), 6.97-7.03 (m, 4H), 7.21-7.30 (m, 3H), 7.37 (s, 1H), 7.70 (s,1H), 10.00 (s, 1H); ESIMS m/e 410 (M⁺+1).

Elemental Analyses for C₂₂H₂₃N₃O₅: Calculated: C, 64.54; H, 5.66; N,10.26. Found: C, 64.25; H, 5.63; N, 10.17.

EXAMPLE 52-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(ethyloxy)acetamide

Following the procedure as described in the example 2, compound 2Ae wassynthesized, as a yellow solid in 91% yield, from 1A andO-ethylhydroxylamine hydrochloride. mp 176.0-178.0° C.; IR(KBr) 3414,3157, 1691, 1677, 1623 cm⁻¹; ¹H NMR (DMSO-d₆) δ 0.97-1.21 (m, 6H), 2.90(q, J=6.8 Hz, 2H), 3.73 (q, J=7.0 Hz, 2H), 4.57 (s, 2H), 5.51 (s, 2H),6.54-6.58 (m, 1H), 6.97-7.09 (m, 4H), 7.21-7.30 (m, 3H), 7.74 (s, 1H),8.11 (s, 1H), 10.93 (s, 1H); ESIMS m/e 424 (M⁺+1).

Elemental Analyses for C₂₃H₂₅N₃O₅: Calculated: C, 65.24; H, 5.95; N,9.92. Found: C, 65.03; H, 6.18; N, 9.78.

EXAMPLE 62-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(2-propenyloxy)acetamide

Following the procedure as described in the Example 2, compound 2Af wassynthesized, as a yellow solid in 91% yield, from 1A andO-(allyl)hydroxylamine hydrochloride. mp 175.0-177.0° C.; IR(KBr) 3360,1680, 1642 cm⁻¹; ¹H NMR (DMSO-d₆) δ 1.04 (t, J=7.1 Hz, 3H), 2.90 (q,J=7.1 Hz, 2H), 4.21 (d, J=5.6 Hz, 2H), 4.56 (s, 2H), 5.06-5.16 (m, 2H),5.51 (s, 2H), 5.75-5.85 (m, 1H), 6.54-6.57 (m, 1H), 6.97-7.09 (m, 4H),7.18-7.32 (m, 3H), 7.71 (s, 1H), 8.09 (s, 1H), 11.01 (s, 1H); ESIMS m/e436 (M⁺+1).

Elemental Analyses for C₂₄H₂₅N₃O₅: Calculated: C, 66.19; H, 5.79; N,9.65. Found: C, 65.98; H, 5.78; N, 9.70.

EXAMPLE 72-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(hydroxy)-N-(2-propyl)acetamide

Following the procedure as described in the Example 2, compound 2Ag wassynthesized, as a white solid in 63% yield, from 1A andN-(2-propyl)hydroxylamine hydrochloride. mp 202° C. (dec.); IR(CHCl₃)3500, 3400, 1700, 1645 cm⁻¹; ¹H NMR (DMSO-d₆) δ 0.93 (d, J=6.2 Hz, 6H),1.03 (t, J=7.2 Hz, 3H), 2.86 (q, J=7.2 Hz, 2H), 3.12-3.17 (m, 1H), 4.80(s, 2H), 5.49 (s, 2H), 6.50-6.53 (m, 1H), 6.97-7.08 (m, 4H), 7.21-7.34(m, 4H), 7.70-7.75 (m, 2H); ESIMS m/e 438 (M⁺+1).

Elemental Analyses for C₂₄H₂₇N₃O₅: Calculated: C, 65.89; H, 6.22; N,9.60. Found: C, 65.95; H, 6.20; N, 9.56.

EXAMPLE 82-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(tert-butyloxy)acetamide

Following the procedure as described in the Example 2, compound 2Ah wassynthesized, as a yellow solid in 78% yield, from 1A andO-(tert-butyl)hydroxylamine hydrochloride. mp 203.0-205.0° C.; IR(KBr)3400, 1691, 1646 cm⁻¹; ¹H NMR (DMSO-d₆) δ 0.93 (s, 9H), 1.04 (t, J=7.0Hz, 3H), 2.89 (q, J=7.0 Hz, 2H), 4.62 (s, 2H), 5.52 (s, 2H), 6.54-6.59(m, 1H), 6.92-6.95 (m, 2H), 7.06-7.10 (m, 2H), 7.19-7.28 (m, 3H), 7.80(s, 1H), 8.19 (s, 1H), 10.35 (s, 1H); ESIMS m/e 452 (M⁺+1).

Elemental Analyses for C₂₅H₂₉N₃O₅: Calculated: C, 66.50; H, 6.47; N.9.31. Found: C, 66.41; H, 6.56; N, 9.62.

EXAMPLE 92-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-[2-(methyl)propyloxy]acetamide

Following the procedure as described in the Example 2, compound 2Ai wassynthesized, as a yellow solid in 65% yield, from 1A andO-(iso-butyl)hydroxylamine hydrochloride. ¹H NMR (DMSO-d₆) δ 0.75 (s,3H), 0.77 (s, 3H), 1.04 (t, J=7.3 Hz, 3H), 1.68 (m, 1H), 2.87-2.93 (m,2H), 3.45 (d, J=6.7 Hz, 2H), 4.57 (s, 2H), 5.51 (s, 2H), 6.55 (d, J=6.6Hz, 1H), 6.98 (d, J=7.2 Hz, 2H), 7.04-7.11 (m, 2H), 7.21-7.30 (m, 3H),7.75 (s, 1H), 8.12 (s, 1H), 10.93 (s, 1H); ESIMS m/e 452 (M⁺+1).

EXAMPLE 102-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(phenylmethyloxy)acetamide

Following the procedure as described in the Example 2, compound 2Aj wassynthesized, as a yellow solid in 90% yield, from 1A andO-benzylhydroxylamine hydrochloride. mp 167.0-169.0° C.; IR(KBr) 3400,3168, 1681, 1643 cm⁻¹; ¹H NMR (DMSO-d₆) δ 1.04 (t, J=6.8 Hz, 3H), 2.91(q, J=6.8 Hz, 2H), 4.58 (s, 2H), 4.74 (s, 2H), 5.52 (s, 2H), 6.54-6.57(m, 1H), 6.99-7.10 (m, 4H), 7.22-7.29 (m, 8H), 7.67 (s, 1H), 8.05 (s,1H), 11.12 (s, 1H); ESIMS m/e 486 (M⁺+1).

Elemental Analyses for C₂₈H₂₇N₃O₅: Calculated: C, 69.26; H, 5.61; N,8.65. Found: C, 69.12; H, 5.54; N, 8.75.

EXAMPLE 112-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(methyl)-N-(phenylmethyloxy)acetamide

Methyl iodide (0.116 mL, 218 mmol) was added to a stirred mixture of 2Aj(101 mg, 0.208 mmol) and K₂CO₃ (57.5 mg, 0.416 mmol) in anhydrous DMF (2mL) at ambient temperature under a nitrogen atmosphere. The resultantmixture was stirred for 4 h. DNF was evaporated in vacuo and the residuewas subject to chromatography on silica [gradient 0-50% EtOAc/CH₂Cl₂,then 3% CH₃OH in EtOAc/CH₂Cl₂ (1/1)] to provide 2Ak (85.0 mg) as a solidin 82% yield. mp 186.5-188.5° C.; IR(CHCl₃) 3500, 3400, 1698, 1645 cm⁻¹;¹H NMR (CDCl₃) δ 1.19 (t, J=7.4 Hz, 3H), 2.94 (q, J=7.4 Hz, 2H), 3.27(s, 3H), 4.78 (s, 2H), 4.89 (s, 2H), 5.34 (s, 2H), 5.40 (br s, 1H),6.26-6.30 (m, 1H), 6.45 (br s, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.96-7.04(m, 3H), 7.25-7.38 (m, 3H), 7.40 (br s, 5H); ESIMS m/e 500 (M⁺+1).

Elemental Analyses for C₂₉H₂₉N₃O₅: Calculated: C, 69.72; H, 5.85; N,8.41. Found: C, 69.80; H, 5.98; N, 8.32.

EXAMPLE 122-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(phenyloxy)acetamide

Following the procedure as described in the Example 2, compound 2Al wassynthesized, as a yellow solid in 80% yield, from 1A andO-phenylhydroxylamine hydrochloride. mp 205° C. (dec.); IR(KBr) 3500,3400, 1690, 1675, 1645 cm⁻¹; ¹H NMR (DMSO-d₆) δ 1.03 (t, J=7.1 Hz, 3H),2.91 (br q, J=7.1 Hz, 2H), 4.80 (s, 2H), 5.53 (s, 2H), 6.69-7.02 (m,6H), 7.12-7.30 (m, 7H), 7.85 (s, 1H), 8.20 (s, 1H), 11.75 (s, 1H); ESIMSm/e 472 (M⁺+1).

Elemental Analyses for C₂₇H₂₅N₃O₅: Calculated: C, 68.78; H, 5.34; N,8.91. Found: C, 68.97; H, 5.29; N, 9.02.

EXAMPLE 132-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(methyl)-N-(phenyloxy)acetamide

Following the procedure as described in the Example 11, compound 2Am wassynthesized, as a yellow solid in 76% yield, from 2Al. mp 146.0-147.5°C.; ¹H NMR (CDCl₃) δ 1.19 (t, J=7.4 Hz, 3H), 2.93 (q, J=7.4 Hz, 2H),3.34 (s, 3H), 4.92 (s, 2H), 5.34 (s, 2H), 5.50 (br s, 1H), 6.51 (d,J=7.9 Hz, 1H), 6.55 (br s, 1H), 6.83 (d, J=8.1 Hz, 1H), 7.00-7.18 (m,6H), 7.24-7.40 (m, 5H); ESIMS m/e 486 (M⁺+1).

EXAMPLE 142-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(cyclohexyl)-N-(hydroxy)acetamide

Following the procedure as described in the Example 2, compound 2An wassynthesized, as a yellow solid in 74% yield, from 1A andN-cyclohexylhydroxylamine hydrochloride. mp 210° C. (dec.); IR(CHCl₃)3500, 3400, 1700, 1644 cm⁻¹; ¹H NMR (DMSO-d₆) δ 0.97-1.20 (m, 4H), 1.06(t, J=7.2 Hz, 3H), 1.50-1.71 (m, 6H), 2.80-2.91 (m, 3H), 4.81 (s, 2H),5.51 (s, 2H), 6.53 (d, J=7.7 Hz, 1H), 7.00-7.10 (m, 4H), 7.21-7.32 (m,3H), 7.35 (s, 1H), 7.72 (s, 1H), 7.78 (d, J=5.5 Hz, 1H); ESIMS m/e 478(M⁺+1).

Elemental Analyses for C₂₇H₃₁N₃O₅: Calculated: C, 67.91; H, 6.54; N,8.80. Found: C, 67.72; H, 6.63; N, 8.95.

EXAMPLE 152-[[3-(2-Amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(hydroxy)acetamide

Following the experimental procedure as described in Example 1. 2Ba wasobtained as a white solid in 64% yield. mp 187-189° C.; ¹H NMR (DMSO-d₆)δ 10.98 (s, 1H), 8.96 (s, 1H), 7.34 (s, 1H), 7.20 (m, 3H), 6.91 (m, 5H),6.41 (s, 1H), 5.34 (s, 2H), 4.55 (s, 2H), 3.62 (s, 2H), 2.73 (m, 2H),0.99 (t, J=7.0 Hz, 3H); ESIMS m/e 382 (M⁺+1).

Elemental Analyses for C₂₁H₂₃N₃O₄.025(H₂O): Calculated: C, 65.36; H,6.14; N, 10.89. Found: C, 65.37; H, 6.27; N, 10.90.

EXAMPLE 162-[[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]-N-(hydroxy)-N-(phenylmethyl)acetamide

Following the procedure as described in Example 2, compound 2Bb wassynthesized from 1A and N-phenylhydroxylamine hydrochloride.

We claim:
 1. An indole compound represented by the formula (I), or apharmaceutically acceptable salt, solvate, or prodrug thereof;

wherein; R₁ is the group —(L₁)—R₁₁; where, —(L₁)— is an alkylene chainof 1 to 8 carbon atoms and where R₁₁ is (CH₂)_(m)R₁₂; m is an integerfrom 1 to 6;

R₁₂ is n is an integer from 0 to 2; R₁₃ is selected from C₁ to C₈ alkyl;p is an integer from 0 to 2; R₂ is hydrogen, or a C₁-C₄ alkyl; R₃ is—(L₃)—Z, where —L₃)— is a bond, and Z is the group represented by theformulae,

R₄ is the group, —(L_(h))-(hydroxyfunctional amide); wherein —(L_(h))—,is represented by the formula

Q₂ is —O—; R₄₀ is independently selected from hydrogen and C₁-C₈ alkyl;

Hydroxy functional amide is the group R_(4a) is OH; R_(4b) is selectedfrom hydrogen or C₁-C₈ alkyl; R₅ is the group, —(L_(a))-(acidic group);wherein —(L_(a))—, is

R₅₄ and R₅₅ are each independently hydrogen or C₁-C₈ alkyl; (acidicgroup) is —CO₂H; R₆ and R₇ are each independently selected fromhydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl.
 2. The compoundof claim 1 wherein R₂ is C₁-C₄ alkyl.
 3. The compound of claim 1 whereinthe hydroxyfunctional amide linker group, —(L_(h))—, for R₄ is adivalent group selected from,


4. The compound of claim 1 wherein the acid linker, —(L_(a))—, for R₅ isthe group represented by the formula;

wherein R₅₄, and R₅₅, are both hydrogen.
 5. The compound of claim 1wherein R₄ is the group, —(L_(c))-(hydroxyfunctional amide group) andwherein the (hydroxyfunctional amide group) is:

and R^(4a) is the group OH; and wherein R^(4b) is (C₁-C₆)alkyl.
 6. Apharmaceutical formulation comprising a indole compound as claimed inclaim 1 together with a pharmaceutically acceptable carrier or diluenttherefor.
 7. A method of treating rheumatoid arthritis in a mammalwherein the method comprises administering to said mammal atherapeutically effective amount of an indole compound as claimed inclaim 1.